Chromatin accessibility and transcriptional landscape in PK-15 cells during early exposure to Aflatoxin B1.

Aflatoxin B1 (AFB1) not only causes significant losses in livestock production but also poses a serious threat to human health. It is the most carcinogenic among known chemicals. Pigs are more susceptible to AFB1 and experience a higher incidence. However, the molecular mechanism of the toxic effect of AFB1 remains unclear. In this study, we used assay for transposase-accessible chromatin using sequencing (ATAC-seq) and RNA-seq to uncover chromatin accessibility and gene expression dynamics in PK-15 cells during early exposure to AFB1. We observed that the toxic effects of AFB1 involve signaling pathways such as p53, PI3K-AKT, Hippo, MAPK, TLRs, apoptosis, autophagy, and cancer pathways. Basic leucine zipper (bZIP) transcription factors (TFs), including AP-1, Fos, JunB, and Fra2, play a crucial role in regulating the biological processes involved in AFB1 challenge. Several new TFs, such as BORIS, HNF1b, Atf1, and KNRNPH2, represent potential targets for the toxic mechanism of AFB1. In addition, it is crucial to focus on the concentration of intracellular zinc ions. These findings will contribute to a better understanding of the mechanisms underlying AFB1-induced nephrotoxicity and offer new molecular targets.

Lactate drives epithelial-mesenchymal transition in diabetic kidney disease via the H3K14la/KLF5 pathway.

High levels of urinary lactate are an increased risk of progression in patients with diabetic kidney disease (DKD). However, it is still unveiled how lactate drive DKD. Epithelial-mesenchymal transition (EMT), which is characterized by the loss of epithelial cells polarity and cell-cell adhesion, and the acquisition of mesenchymal-like phenotypes, is widely recognized a critical contributor to DKD. Here, we found a switch from oxidative phosphorylation (OXPHOS) toward glycolysis in AGEs-induced renal tubular epithelial cells, thus leading to elevated levels of renal lactic acid. We demonstrated that reducing the lactate levels markedly delayed EMT progression and improved renal tubular fibrosis in DKD. Mechanically, we observed lactate increased the levels of histone H3 lysine 14 lactylation (H3K14la) in DKD. ChIP-seq & RNA-seq results showed histone lactylation contributed to EMT process by facilitating KLF5 expression. Moreover, KLF5 recognized the promotor of cdh1 and inhibited its transcription, which accelerated EMT of DKD. Additionally, nephro-specific knockdown and pharmacological inhibition of KLF5 diminished EMT development and attenuated DKD fibrosis. Thus, our study provides better understanding of epigenetic regulation of DKD pathogenesis, and new therapeutic strategy for DKD by disruption of the lactate-drived H3K14la/KLF5 pathway.

Do tougher drinking policies affect men's smoking behavior - Evidence from China.

In 2011, China implemented tougher driving-under-the-influence laws, which criminalized driving under the influence of alcohol for the first time and increased penalties. This paper provides the first comprehensive analysis of the effects of stricter drinking policies on men's smoking behavior by using data from the 2010 and 2012 waves of the China Family Panel Studies. The results show that stricter drinking policies reduced smoking initiation and the number of cigarettes smoked per day among men by reducing the frequency and quantity of alcohol consumption. Heterogeneity analyses show that the impact of the policy is more pronounced not only for men aged 41-55, but also for men who have higher educational qualifications, who are employed, or who are not members of the Communist Party.

Mechanisms of Gills Response to Cadmium Exposure in Greenfin Horse-Faced Filefish (Thamnaconus septentrionalis): Oxidative Stress, Immune Response, and Energy Metabolism.

Cadmium (Cd) pollution has become a global issue due to industrial and agricultural developments. However, the molecular mechanism of Cd-induced detrimental effects and relevant signal transduction/metabolic networks are largely unknown in marine fishes. Here, greenfin horse-faced filefish (Thamnaconus septentrionalis) were exposed to 5.0 mg/L Cd up to 7 days. We applied both biochemical methods and multi-omics techniques to investigate how the gills respond to Cd exposure. Our findings revealed that Cd exposure caused the formation of reactive oxygen species (ROS), which in turn activated the MAPK and apoptotic pathways to alleviate oxidative stress and cell damage. Glycolysis, protein degradation, as well as fatty acid metabolism might assist to meet the requirements of nutrition and energy under Cd stress. We also found that long-term (7 days, "long-term" means compared to 12 and 48 h) Cd exposure caused the accumulation of succinate, which would in turn trigger an inflammatory response and start an immunological process. Moreover, ferroptosis might induce inflammation. Overall, Cd exposure caused oxidative stress, energy metabolism disturbance, and immune response in greenfin horse-faced filefish. Our conclusions can be used as references for safety risk assessment of Cd to marine economic fishes.

Effect of low anterior resection syndrome on quality of life in colorectal cancer patients: A retrospective observational study.

BACKGROUND: Low anterior resection syndrome (LARS) is a common complication of anus-preserving surgery in patients with colorectal cancer, which significantly affects patients' quality of life. AIM: To determine the relationship between the incidence of LARS and patient quality of life after colorectal cancer surgery and to establish a LARS prediction model to allow perioperative precision nursing. METHODS: We reviewed the data from patients who underwent elective radical resection for colorectal cancer at our institution from April 2013 to June 2020 and completed the LARS score questionnaire and the European Organization for Research and Treatment of Cancer Core Quality of Life and Colorectal Cancer Module questionnaires. According to the LARS score results, the patients were divided into no LARS, mild LARS, and severe LARS groups. The incidence of LARS and the effects of this condition on patient quality of life were determined. Univariate and multivariate analyses were performed to identify independent risk factors for the occurrence of LARS. Based on these factors, we established a risk prediction model for LARS and evaluated its performance. RESULTS: Among the 223 patients included, 51 did not develop LARS and 171 had mild or severe LARS. The following quality of life indicators showed significant differences between patients without LARS and those with mild or severe LARS: Physical, role, emotional, and cognitive function, total health status, fatigue, pain, shortness of breath, insomnia, constipation, and diarrhea. Tumor size, partial/total mesorectal excision, colostomy, preoperative radiotherapy, and neoadjuvant chemotherapy were identified to be independent risk factors for LARS. A LARS prediction model was successfully established, which demonstrated an accuracy of 0.808 for predicting the occurrence of LARS. CONCLUSION: The quality of life of patients with LARS after colorectal cancer surgery is significantly reduced.

CLMP is a tumor suppressor that determines all-trans retinoic acid response in colorectal cancer.

CAR-like membrane protein (CLMP) is a tight junction-associated protein whose mutation is associated with congenital short bowel syndrome (CSBS), but its functions in colorectal cancer (CRC) remain unknown. Here, we demonstrate that CLMP is rarely mutated but significantly decreased in CRC patients, and its deficiency accelerates CRC tumorigenesis, growth, and resistance to all-trans retinoic acid (ATRA). Mechanistically, CLMP recruits ß-catenin to cell membrane, independent of cadherin proteins. CLMP-mediated ß-catenin translocation inactivates Wnt(Wingless and INT-1)/ß-catenin signaling, thereby suppressing CRC tumorigenesis and growth in ApcMin/+, azoxymethane/dextran sodium sulfate (AOM/DSS), and orthotopic CRC mouse models. As a direct target of Wnt/ß-catenin, cytochrome P450 hydroxylase A1 (CYP26A1)-an enzyme that degrades ATRA to a less bioactive retinoid-is upregulated by CLMP deficiency, resulting in ATRA-resistant CRC that can be reversed by administering CYP26A1 inhibitor. Collectively, our data identify the anti-CRC role of CLMP and suggest that CYP26A1 inhibitor enable to boost ATRA's therapeutic efficiency.

Combination of ultra-micro angiography and sound touch elastography for diagnosis of primary Sjögren's syndrome: a diagnostic test.

Background: Primary Sjogren's syndrome (PSS) is a prevalent systemic autoimmune disease. However, the current gold standard diagnostic method is invasive, increasing the difficulty of patient acceptance and then delaying treatment. Therefore, a non-invasive, convenient, and effective diagnostic method is required. Although salivary gland ultrasonography (SGUS) is a good choice, previous studies have not found suitable parameters to diagnose PSS. Salivary gland involvement in patients with PSS leads to changes in gland stiffness and vascularization, so we combined sound touch elastography (STE) and ultra-microangiography (UMA) to demonstrate the diagnostic effectiveness of ultrasonography in PSS. Methods: This prospective study included 27 patients with PSS and 20 healthy controls, with all participants forming a random series. Major salivary glands were examined with UMA and STE. Color pixel percentage (CPP), shear wave velocity (SWV), and Young's modulus values were investigated, and the combination of these parameters was evaluated by logistic regression analysis. Results: For Young's modulus and SWV in the elasticity index, combined evaluation of both parotid glands and submandibular glands yielded an area under the receiver operating characteristic (ROC) curve (AUC) and confidence interval (CI) of 0.819, 0.699-0.938 and 0.801, 0.677-0.925, respectively. The levels of CPP in the parotid glands were significantly elevated (P<0.003) among patients compared to those in the control group, whereas the CPP values in the submandibular glands were not statistically different (P>0.086). We evaluated the elasticity values of the total 4 glands and the CPP of parotid glands together by logistic regression modeling. The ROC curve yielded an AUC of 0.954 (95% CI: specificity 0.849-0.994) which showed the best accuracy, with 92.6% sensitivity and 85.0% specificity. Conclusions: The use of STE and UMA to examine the salivary glands may aid in the diagnosis of PSS, and their combination may be a promising method. This is good news for patients with PSS who are not suitable or unwilling to undergo labial gland biopsy.

Exosomes combined with biomaterials in the treatment of spinal cord injury.

Spinal cord injury (SCI) is a serious and disabling disease with a high mortality rate. It often leads to complete or partial sensory and motor dysfunction and is accompanied by a series of secondary outcomes, such as pressure sores, pulmonary infections, deep vein thrombosis in the lower extremities, urinary tract infections, and autonomic dysfunction. Currently, the main treatments for SCI include surgical decompression, drug therapy, and postoperative rehabilitation. Studies have shown that cell therapy plays a beneficial role in the treatment of SCI. Nonetheless, there is controversy regarding the therapeutic effect of cell transplantation in SCI models. Meanwhile exosomes, as a new therapeutic medium for regenerative medicine, possess the advantages of small size, low immunogenicity, and the ability to cross the blood-spinal cord barrier. Certain studies have shown that stem cell-derived exosomes have anti-inflammatory effects and can play an irreplaceable role in the treatment of SCI. In this case, it is difficult for a single treatment method to play an effective role in the repair of neural tissue after SCI. The combination of biomaterial scaffolds and exosomes can better transfer and fix exosomes to the injury site and improve their survival rate. This paper first reviews the current research status of stem cell-derived exosomes and biomaterial scaffolds in the treatment of SCI respectively, and then describes the application of exosomes combined with biomaterial scaffolds in the treatment of SCI, as well as the challenges and prospects.

Diagnostic accuracy of contrast-enhanced ultrasound synchronized with shear wave elastography in the differential diagnosis of benign and malignant breast lesions: a diagnostic test.

Background: Breast cancer (BC) is one of the most common malignancies affecting women. Timely and accurate diagnosis is crucial for treatment and prognosis. Some studies have found that elastography combined with microperfusion characteristics, which are mostly described by contrast-enhanced ultrasound (CEUS), could help in the diagnosis of breast lesions. This study aimed to assess the diagnostic performance of CEUS synchronized with shear wave elastography (SWE) in discriminating between benign and malignant breast lesions by using real-time contrast elastography images to analyze shell elasticity and contrast intensity. Methods: A total of 26 pathologically confirmed breast lesions in 26 patients were retrospectively reviewed. Each patient underwent conventional B-mode ultrasound, CEUS, and then SWE data was obtained from a frame of image that was almost identical to the B-mode and CEUS images when acquiring time to peak (TTP). Breast lesions were evaluated based on the Breast Imaging Reporting and Data System (BI-RADS) and quantitative characteristics that describe the stiffness and intensity of contrast of the 1.0-3.0 mm shell region. Quantitative aspects of the inner lesions and shell on the elastogram included the maximum (Emax), mean (Emean), and minimum (Emin) Young's moduli. Quantitative enhanced features included maximum (Imax) and mean (Imean) intensity. We took postoperative pathological results as the gold standard. Receiver operating characteristic (ROC) curves were used to compare the diagnostic efficacy of the 2 examination modalities, either alone or in combination. Results: The age of the patients ranged from 23 to 76 years, with a 42.5-year average age. In all breast lesions, 19 were benign and 7 were malignant. SWE synchronized with CEUS can effectively improve the diagnostic performance of breast lesions, and Emean + Imean and Emax + Emean + Imean of shell at 1.0 mm both had the highest area under the curve (AUC) of 0.86 [95% confidence interval (CI): 0.67, 0.96], with the sensitivity and specificity of 71.43% and 89.47%, respectively. Conclusions: The combination of CEUS and SWE has a better diagnostic value in differentiating benign and malignant breast lesions compared to separate techniques.

A decellularized spinal cord extracellular matrix-gel/GelMA hydrogel three-dimensional composite scaffold promotes recovery from spinal cord injury via synergism with human menstrual blood-derived stem cells.

Spinal cord injury (SCI), as a serious disabling disease, is still haunted by lacking of effective treatments. We previously found that transplantation of menstrual blood-derived mesenchymal stem cells (MenSCs) promoted axon regeneration in rats with SCI, while the abominable microenvironment after the SCI inhibited the survival of stem cells after transplantation. Biomaterials can support the activity of stem cells and accelerate the functional reconstruction of the injured spinal cord. In this study, we constructed a novel composite scaffold consisting of the decellularized spinal cord extracellular matrix-gel (DSCG) and the GelMA hydrogel, which harbored high water retention, wettability, degradability and soft mechanical property. In vitro, the DSCG/GelMA composite scaffold provided a dual bionic microenvironment with optimized bioactive components and favorable microstructures for the adhesion, proliferation and differentiation of MenSCs. After that, we prepared MenSC-encapsulated DSCG/GelMA composite scaffolds to bridge the 2 mm gap in rats with completely transected SCI. The in vivo results showed that the combined use of the DSCG/GelMA composite scaffold with MenSCs improved the motor function, reduced the inflammatory response, promoted neuronal differentiation, and inhibited the proliferation of reactive astrocytes after spinal cord injury. Altogether, our study provided a promising novel therapeutic option of using bioactive materials synergistic with stem cells for the treatment of SCI.

YY1 accelerates oral squamous cell carcinoma progression through long non-coding RNA Kcnq1ot1/microRNA-506-3p/SYPL1 axis.

OBJECTIVE: Ying Yang1 (YY1) has already been discussed in oral squamous cell carcinoma (OSCC), but the knowledge about its mediation on long non-coding RNA KCNQ1 overlapping transcript 1/microRNA-506-3p/synaptophysin like 1 (Kcnq1ot/miR-506-3p/SYPL1) axis in OSCC is still in its infancy. Hence, this article aims to explain the mechanism of YY1/Kcnq1ot1/miR-506-3p/SYPL1 axis in OSCC development. METHODS: YY1, Kcnq1ot1, miR-506-3p and SYPL1 expression levels were determined in OSCC tissues. The potential relation among YY1, Kcnq1ot1, miR-506-3p and SYPL1 was explored. Cell progression was observed to figure out the actions of depleted YY1, Kcnq1ot1 and SYPL1 and restored miR-506-3p in OSCC. OSCC tumorigenic ability in mice was examined. RESULTS: Elevated YY1, Kcnq1ot1 and SYPL1 and reduced miR-506-3p were manifested in OSCC. YY1 promoted Kcnq1ot1 transcription and up-regulated Kcnq1ot1 expression, thereby promoting OSCC cell procession. Silencing Kcnq1ot1 or elevating miR-506-3p delayed OSCC cell progression and silencing Kcnq1ot1 impeded tumorigenic ability of OSCC cells in mice. YY1-mediated Kcnq1ot1 sponged miR-506-3p to target SYPL1. CONCLUSION: YY1 promotes OSCC cell progression via up-regulating Kcnq1ot1 to sponge miR-506-3p to elevate SYPL1, guiding a novel way to treat OSCC.

Creatine promotes cancer metastasis through activation of Smad2/3.

As one of the most popular nutrient supplements, creatine has been highly used to increase muscle mass and improve exercise performance. Here, we report an adverse effect of creatine using orthotopic mouse models, showing that creatine promotes colorectal and breast cancer metastasis and shortens mouse survival. We show that glycine amidinotransferase (GATM), the rate-limiting enzyme for creatine synthesis, is upregulated in liver metastases. Dietary uptake, or GATM-mediated de novo synthesis of creatine, enhances cancer metastasis and shortens mouse survival by upregulation of Snail and Slug expression via monopolar spindle 1 (MPS1)-activated Smad2 and Smad3 phosphorylation. GATM knockdown or MPS1 inhibition suppresses cancer metastasis and benefits mouse survival by downregulating Snail and Slug. Our findings call for using caution when considering dietary creatine to improve muscle mass or treat diseases and suggest that targeting GATM or MPS1 prevents cancer metastasis, especially metastasis of transforming growth factor beta receptor mutant colorectal cancers.

Effects of government cash subsidies on health risk behaviors of the rural elderly: Evidence from social pension expansions in China.

INTRODUCTION: There is relatively little research on the impact of government cash subsidies on health risk behaviors of the elderly in China. We thus analyzed the effect of pension subsidies on the smoking and drinking behaviors of rural elderly using a pension scheme introduced in rural China in 2009. METHODS: Based on panel data from the Chinese Longitudinal Healthy Longevity Survey (CLHLS) in 2008 and 2011, a Difference-in-Differences (DID) method was applied to comprehensively analyze the impact of the new agricultural insurance on the health risk behaviors of the rural elderly. In order to solve possible sample selection biases, the Propensity Score Matching with Difference-in-Differences (PSM-DID) approach was used. RESULTS: We found that the implementation of the government cash subsidies clearly promoted smoking rather than drinking behavior among rural older adults. Specifically, the government cash subsidies facilitated smokers to smoke an additional 2.9 cigarettes/day, and the impact of government cash subsidies on the average cigarettes/day among smokers was more pronounced among the male elderly, lower age elderly, higher income elderly, and elderly with intact instrumental activities of daily living (IADL). CONCLUSIONS: In order to reduce the negative externalities of old-age subsidies, the government should place some restrictions on the use of cash subsidies for tobacco purchase by the elderly.

Silver-amplified fluorescence immunoassay via aggregation-induced emission for detection of disease biomarker.

Development of simple, robust, and reliable detection strategy of disease biomarkers holds tremendous promise for early clinical diagnosis and prognosis of diseases. In this work, through combining a silver nanoparticle (AgNP) linked immunoassay and aggregation induced emission (AIE)-based fluorogenic Ag+ probe, we developed a silver-amplified fluorescence immunoassay for the detection of disease biomarkers. This method overcame the intrinsic limitations of enzymes as the dissolution of AgNPs generated numerous Ag+, which could switch on the fluorogenic Ag+ probe driven by tetrazolate-Ag+ complexation. As a proof of concept, our method could be used for determining α-fetoprotein (AFP) with a linear relationship in concentrations ranging from 0.1 ng mL-1 to 5 µg mL-1 and a low limit of detection of 42 pg mL-1. Our method was successfully confirmed for the detection of AFP in real serum samples from hepatocellular carcinoma (HCC) patients, demonstrating the great potential for clinical diagnosis.

Retroperitoneal parasitic fetus: A case report.

BACKGROUND: Fetus-in-fetu (FIF) is an extremely rare congenital abnormal mass, in which a normal fetus's vertebral axis frequently connected with malformed fetus around this axis. Here, we report the case of a male infant aged 26 d presenting with retroperitoneal parasitic fetus. CASE SUMMARY: In a prenatal examination, we first detected an abdominal mass measuring 7.8 cm × 5.1 cm × 6.8 cm in a mother's abdomen at 25 gestational weeks and teratoma was suspected. After the fetal was born, we did a magnetic resonance imaging (MRI) and ultrasonography on him and saw a distinctive limb with five-toes. According to the result of MRI, ultrasonography and postoperative pathology, he finally was diagnosed with FIF. CONCLUSION: A laparotomy was performed at 26 d of age with excision of the retroperitoneal cystic tumor, which measured about 10 cm in diameter. According to the result of imaging and histological test, FIF was confirmed.

SSPH I, a Novel Anti-Cancer Saponin, Inhibits Autophagy and Induces Apoptosis via ROS Accumulation and ERK1/2 Signaling Pathway in Hepatocellular Carcinoma Cells.

INTRODUCTION: Saponin of Schizocapsa plantaginea Hance I (SSPH I), a novel bioactive phytochemical isolated from the rhizomes of Schizocapsa plantaginea, has been demonstrated to exhibit anti-cancer activity against various tumors in preclinical studies. However, the molecular mechanisms involved in the suppression of hepatocellular carcinoma (HCC) are poorly understood. The present study aimed at analyzing the effects of SSPH I on autophagy and apoptosis in vitro. METHODS: MTT and colony forming assays were used to detect cell viability and cell proliferation. Hoechst 33,258 staining and flow cytometry were used to determine apoptosis and ROS production. The apoptosis and autophagy-related protein expression levels were evaluated via Western blot assay. Characteristics of autophagy and apoptosis were observed by transmission electron microscopy. Lysosomal activity was stained with Lyso-Tracker Red and Magic Red Cathepsin B. RESULTS: The results showed that SSPH I exhibited potent anti-cancer activity and proliferation in HepG2 and BEL-7402 cells and inhibited HepG2 cells through inhibiting autophagy and promoting apoptosis. The mechanistic study indicated that the inhibition of autophagy of SSPH I was mediated by blocking autophagosome-lysosome fusion. Additionally, we found that SSPH I could mediate the activation of MAPK/ERK1/2 signaling pathway, and the use of NAC (ROS inhibitor) and U0126 (MEK1/2 inhibitor) converted the effect of SSPH I on apoptosis and autophagy in HepG2 cells. CONCLUSION: These data suggest that SSPH I induces tumor cells apoptosis and reduces autophagy in vitro by inducing ROS and activating MAPK/ERK1/2 signaling pathway, indicating that SSPH I might be a novel agent for the treatment of HCC.

The epigallocatechin gallate derivative Y6 reduces the cardiotoxicity and enhances the efficacy of daunorubicin against human hepatocellular carcinoma by inhibiting carbonyl reductase 1 expression.

ETHNOPHARMACOLOGICAL RELEVANCE: Green tea is the most ancient and popular beverage worldwide and its main constituent epigallocatechin-3-gallate (EGCG) has a potential role in the management of cancer through the modulation of cell signaling pathways. However, EGCG is frangible to oxidation and exhibits low lipid solubility and bioavailability, and we synthesized a derivative of EGCG in an attempt to overcome these limitations. AIM OF THE STUDY: The anthracycline antibiotic daunorubicin (DNR) is a potent anticancer agent. However, its severe cardiotoxic limits its clinical efficacy. Human carbonyl reductase 1 (CBR1) is one of the most effective human reductases for producing hydroxyl metabolites and thus may be involved in increasing the cardiotoxicity and decreasing the antineoplastic effect of anthracycline antibiotics. Accordingly, in this study, we investigated the co-therapeutic effect of Y6, a novel and potent adjuvant obtained by optimization of the structure of EGCG. MATERIAL AND METHODS: The cellular concentrations of DNR and its metabolite DNRol were measured by HPLC to determine the effects of EGCG and Y6 on the inhibition of DNRol formation. The cytotoxic effects of EGCG and Y6 were tested by MTT assay in order to identify non-toxic concentrations of them. To understand their antitumor and cardioprotective mechanisms, hypoxia-inducible factor-1α (HIF-1α) and CBR1 protein expression was measured via Western blotting and immunohistochemical staining while gene expression was analyzed using RT-PCR. Moreover, PI3K/AKT and MEK/ERK signaling pathways were analyzed via Western blotting. HepG2 xenograft model was used to detect the effects of EGCG and Y6 on the antitumor activity and cardiotoxicity of DNR in vivo. Finally, to obtain further insight into the interactions of Y6 and EGCG with HIF-1α and CBR1, we performed a molecular modeling. RESULTS: Y6(10 µg/ml or 55 mg/kg) decreased the expression of HIF-1α and CBR1 at both the mRNA and protein levels during combined drug therapy in vitro as well as in vivo, thereby inhibiting formation of the metabolite DNRol from DNR, with the mechanisms being related to PI3K/AKT and MEK/ERK signaling inhibition. In a human carcinoma xenograft model established with subcutaneous HepG2 cells, Y6(55 mg/kg) enhanced the antitumor effect and reduced the cardiotoxicity of DNR more effectively than EGCG(40 mg/kg). CONCLUSIONS: Y6 has the ability to inhibit CBR1 expression through the coordinate inhibition of PI3K/AKT and MEK/ERK signaling, then synergistically enhances the antitumor effect and reduces the cardiotoxicity of DNR.

Circular RNA hsa_circ_001783 regulates breast cancer progression via sponging miR-200c-3p.

Increasing evidence suggests circular RNAs (circRNAs) exert critical functions in tumor progression via sponging miRNAs (microRNAs). However, the role of circRNAs in breast cancer remains unclear. Here we systematically analyzed the circular RNAs in breast cancer based on their characteristic in sponging disease-specific miRNAs and identified hsa_circ_001783 as a top ranked circRNA in our computation and verified its high expression in both breast cancer cells and cancer tissue. A higher level of hsa_circ_001783 was significantly correlated with heavier tumor burden and poorer prognosis of patients with breast cancer. Knockdown of this circRNA remarkably inhibited the proliferation and invasion of breast cancer cells. Importantly, hsa_circ_001783 promoted progression of breast cancer cells via sponging miR-200c-3p. Taken together, hsa_circ_001783 may serve as a novel prognostic and therapeutic target for breast cancer.

The BET bromodomain inhibitor apabetalone induces apoptosis of latent HIV-1 reservoir cells following viral reactivation.

The persistence of latent HIV-1 reservoirs throughout combination antiretroviral therapy (cART) is a major barrier on the path to achieving a cure for AIDS. It has been shown that bromodomain and extra-terminal (BET) inhibitors could reactivate HIV-1 latency, but restrained from clinical application due to their toxicity and side effects. Thus, identifying a new type of BET inhibitor with high degrees of selectivity and safety is urgently needed. Apabetalone is a small-molecule selective BET inhibitor specific for second bromodomains, and has been evaluated in phase III clinical trials that enrolled patients with high-risk cardiovascular disorders, dyslipidemia, and low HDL cholesterol. In the current study, we examined the impact of apabetalone on HIV-1 latency. We showed that apabetalone (10-50 µmol/L) dose-dependently reactivated latent HIV-1 in 4 types of HIV-1 latency cells in vitro and in primary human CD4+ T cells ex vivo. In ACH2 cells, we further demonstrated that apabetalone activated latent HIV-1 through Tat-dependent P-TEFB pathway, i.e., dissociating bromodomain 4 (BDR4) from the HIV-1 promoter and recruiting Tat for stimulating HIV-1 elongation. Furthermore, we showed that apabetalone (10-30 µmol/L) caused dose-dependent cell cycle arrest at the G1/G0 phase in ACH2 cells, and thereby induced the preferential apoptosis of HIV-1 latent cells to promote the death of reactivated reservoir cells. Notably, cardiovascular diseases and low HDL cholesterol are known as the major side effects of cART, which should be prevented by apabetalone. In conclusion, apabetalone should be an ideal bifunctional latency-reversing agent for advancing HIV-1 eradication and reducing the side effects of BET inhibitors.

Trilobatin as an HIV-1 entry inhibitor targeting the HIV-1 Gp41 envelope.

HIV-1 transmembrane protein gp41 plays a crucial role by forming a stable six-helix bundle during HIV entry. Due to highly conserved sequence of gp41, the development of an effective and safe small-molecule compound targeting gp41 is a good choice. Currently, natural polyanionic ingredients with anti-HIV activities have aroused concern. Here, we first discovered that a glycosylated dihydrochalcone, trilobatin, exhibited broad anti-HIV-1 activity and low cytotoxicity in vitro. Site-directed mutagenesis analysis suggested that the hydrophobic residue (I564) located in gp41 pocket-forming site is pivotal for anti-HIV activity of trilobatin. Furthermore, trilobatin displayed synergistic anti-HIV activities combined with other antiretroviral agents. Trilobatin has a good potential to be developed as a small-molecule HIV-1 entry inhibitor for clinical combination therapy.